Randall Highlights the Evolving Role of Surgery in TGCT Management

R. Lor Randall, MD, FACS

Early efficacy seen with both vimseltinib (DCC-3014) monotherapy and pexidartinib (Turalio) plus surgery in patients with previously unresectable or inoperable diffuse tenosynovial giant cell tumors (TGCT) further supports the use of CSF1R inhibitors as a much-needed alternative to surgery alone, according to R. Lor Randall, MD, FACS. He added that in lieu of robust data on the optimal setting to utilize these agents, it is important to stay informed on the evolving role of surgical intervention in the management of this disease.

The global phase 3 MOTION trial (NCT05059262) is currently evaluating the efficacy and safety of vimseltinib vs placebo in participants with TGCT not amenable to surgery.¹ According to top-line results, the trial met its primary end point, with an objective response rate (ORR) at week 25 of 40% (95% CI, 29%-51%) with vimseltinib (n = 83) vs 0% (95% CI, 0%-9%) with placebo (n = 40; P <.0001).² Moreover, treatment with the agent resulted in statistically significant and clinically meaningful improvements in all key secondary end points of the trial, including ORR per tumor volume score, active range of motion, physical function, stiffness, quality of life (QOL), and pain.

Based on these data, a new drug application for vimseltinib in TGCT is expected to be submitted in the second quarter of 2024, and submission of a marketing authorization application to the European Medicines Agency is expected in the third quarter of 2024.

“We want to raise awareness about the disease, this trial, and the fact that surgery has an evolving modified role in the management of patients with TGCT,” said Randall, who is the David Linn Endowed Chair for Orthopedic Surgery, the chair of the Department of Orthopedic Surgery, and a professor at UC Davis Comprehensive Cancer Center in Sacramento, California. “We’re very excited about this study and [more] data should be forthcoming.”

In an interview with OncLive®, Randall discussed the significance of the MOTION trial and obtaining QOL data for patients with TGCT; explained why RECIST criteria are an optimal objective measure of response in this disease setting; and emphasized that the continued development of CSF1R inhibitors and other nonsurgical interventions require increased communication and collaboration between surgeons and medical oncologists.

OncLive: Please discuss the rationale and significance of the phase 3 MOTION trial in TGCT. Why is it vital to evaluate patient-reported measures such as QOL?

Randall: MOTION is a phase 3 trial [examining] vimseltinib [DCC-3014] at 30 mg twice weekly vs placebo for 24 weeks, and then switch over to all drugs for the following 24 weeks and then potentially maintenance thereafter. The primary end point is overall response rate [ORR] using MRI, but other functional subjective data have been collected, as well. Preliminary data [from the MOTION trial] are favorable.

It is important to point out that for these nonmalignant but locally aggressive tumors, QOL is a very important consideration. QOL is important in the cancer domain, as well; however, when it’s ultimately a mortal disease, QOL sort of falls second. TGCT is not life-threatening in 99.9% of cases, so QOL is the driver. QOL is also subjective, so this study is important. Some tumors will have a good response by RECIST [criteria] with shrinking of the tumor; however, either the adverse effects of the drug or the disease itself may preclude overall improvement from the patient’s perspective.

What tools were used to assess patient-reported outcomes (PROs), and how is this information interpreted given its inherent subjectivity?

The tool being utilized is the PROMIS physical function [PF] score. Numerous things can be measured with the PROMIS PF score, but they’re using the short form. The idea is to get subjective data on how [patients] feel functionally. We’ll also be looking at stiffness, and then the EuroQOL visual analog scale. All of these [assessments] will be done at week 25 to look at improvement. That gives some sort of objective criteria.

The PROMIS database is sort of disease agnostic, meaning that whether it’s an orthopedic condition or a tumor condition, physical function data are out there on populations. [This tool] allows [clinicians to identify] where patients will fall into this range [of physical functioning] relative to the standard deviations of a [given] population, age-controlled and otherwise. That is helpful because patients want to know how they are doing relative to everyone else in society. It gives them that point of reference.

In the Department of Orthopaedic Surgery at UC Davis Health, we take pride in getting that kind of data for our orthopedic patients. [That way,] if they [undergo a] hip replacement or a knee replacement or some sort of procedure, they can understand how they’re doing relative to everyone else in their age group.

What was the rationale for making ORR the primary end point of the MOTION trial?

[Making ORR the primary end point] seems to make the greatest sense because it is measurable using RECIST criteria. Some of us in the solid tumor world jokingly say, “resist RECIST” because we can poke holes in what RECIST tells us. RECIST is basically the size of the tumor, [although] it’s not quite as simple as that. Some patients’ tumors will be a certain size, they’ll get treatment, and that treatment causes the tumor to swell, but kills it. [Despite experiencing] good treatment effect, the tumor is bigger, [so these patients will] have a worse RECIST score even though they’ve got more tumor necrosis. Some people poke holes in RECIST, because they think it isn’t a good surrogate for biologic or pathologic response to a given treatment.

In TGCT, we don’t think that’s the case. These tumors don’t undergo necrosis, they just tend to grow like a weed. In using objective MRI measurements, and therefore, ORR based on RECIST, we’re getting something quantifiable and objective. Although ORR is the primary end point, those other end points of PROs are important, because a patient may experience a shrinkage of their tumor but a worsening of symptoms.

Given the favorable outcomes seen with these CSF1R inhibitors thus far, what next steps should be undertaken to validate their efficacy in TGCT?

One of the things that we surgeons would be interested in is a trial of a neoadjuvant [regimen] vs placebo for patients who are definitively going to surgery. [However], it’s hard to get traction once the drug has come to market. [The MOTION] trial was for patients who were deemed unresectable. Now, “unresectable” is a relative term; [it is more accurately framed as] resectable at what cost? Some people are willing to undergo an aggressive surgery irrespective of the risks, and others are not willing to do so. The threshold [for being labelled] “unresectable” is patient dependent in this case. [Therefore], using [vimseltinib] in a neoadjuvant fashion and randomizing it to see whether you get better local control would be very helpful.

Why is it important to be aware of this condition and its evolving treatment options?

Medical oncologists will likely see [more of] this condition in the next 5 years than they have in the past 5 years because there are [more approaches available. We] now have pexidartinib [(Turalio) in combination with surgery], and vimseltinib is likely to come to market. [Accordingly, medical oncologists] will be asked to help the orthopedic surgeon in managing this disease [more often].

It's important that there’s good communication between the medical oncologist and the surgeon. Surgery still does have a role [in managing TGCT] and we don’t have a data-driven study to inform us about when we would use [these agents] preoperatively vs in an adjuvant setting. There needs to be good communication between the surgeons and the medical oncologist, as I think there will be an uptick in the number of patients seeing a medical oncologist for this benign but locally aggressive disease.

Reference

1. Tap WD, Sharma MG, Vallee M, et al. The MOTION study: a randomized, phase III study of vimseltinib for the treatment of tenosynovial giant cell tumor. Future Oncol. Published online August 18, 2023. doi:10.2217/fon-2023-0238
2. Deciphera Pharmaceuticals announces positive top-line results from MOTION pivotal phase 3 study of vimseltinib in patients with tenosynovial giant cell tumor (TGCT) and updated results from phase 1/2 study of vimseltinib in TGCT. News release. Deciphera Pharmaceuticals, Inc. October 30, 2023. Accessed January 16, 2024. https://investors.deciphera.com/news-releases/news-release-details/deciphera-pharmaceuticals-announces-positive-top-line-results-0